EP2398768B1 - Pyrrolidine derivatives as nk3 receptor antagonists - Google Patents

Pyrrolidine derivatives as nk3 receptor antagonists Download PDF

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Publication number
EP2398768B1
EP2398768B1 EP10704808.4A EP10704808A EP2398768B1 EP 2398768 B1 EP2398768 B1 EP 2398768B1 EP 10704808 A EP10704808 A EP 10704808A EP 2398768 B1 EP2398768 B1 EP 2398768B1
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methyl
phenyl
pyrrolidin
dichloro
methanone
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French (fr)
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EP2398768A1 (en
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Henner Knust
Anja Limberg
Matthias Nettekoven
Hasane Ratni
Claus Riemer
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F Hoffmann La Roche AG
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/16—Anti-Parkinson drugs
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compounds of formula I- A wherein
  • the invention includes all stereoisomeric forms, including individual diastereoisomers and enantiomers of the compound of formula (I) as well as racemic and non-racemic mixtures
  • NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, bipolar disorders, anxiety and attention deficit hyperactivity disorder (ADHD).
  • the three main mammalian tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH 2 .
  • SP substance P
  • NKA neurokinin A
  • NKB neurokinin B
  • the NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain ( Neurosci. Letters, 2000, 283, 185 -188 ; Exp. Opin. Ther. Patents 2000, 10, 939-960 ; Neuroscience, 1996, 74, 403-414 ; Neuropeptides, 1998, 32, 481-488 ) .
  • Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1 % of the world's population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms).
  • an appropriate multireceptor affinity profile might be required for efficacy against positive and negative signs and symptoms.
  • an ideal drug against schizophrenia would preferably have a low dosage allowing once-per-day dosage, due to the low adherence of schizophrenic patients.
  • Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identified potent and selective non-peptide antagonist described for the NK3 tachykinin receptor for the potential treatment of schizophrenia, which was reported in the literature ( Current Opinion in Investigational Drugs, 2001,2(7), 950-956 and Psychiatric Disorders Study 4, Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Massachusetts ).
  • the proposed drug SR 142,801 has been shown in a phase II trial as active on positive symptoms of schizophrenia, such as altered behaviour, delusion, hallucinations, extreme emotions, excited motor activity and incoherent speech, but inactive in the treatment of negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits.
  • neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, as well as in schizophrenia, Exp. Opinion.Ther. Patents (2000), 10(6), 939-960 and Current Opinion in Investigational Drugs, 2001, 2(7), 950-956 956 and Psychiatric Disorders Study 4, Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Massachusetts ) .
  • Objects of the present invention are novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as depression, pain, bipolar disorders, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).
  • illnesses such as depression, pain, bipolar disorders, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).
  • the preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, schizophrenia, bipolar disorders, anxiety and attention deficit hyperactivity disorder (ADHD).
  • lower alkyl denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
  • Preferred lower alkyl groups are groups with 1-4 carbon atoms.
  • lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CF 2 CF 3 and the like.
  • Preferred lower alkyl substituted by halogen groups are groups having 1-4 carbon atoms.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl denotes a saturated carbon ring containing from 3-6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclpentyl or cyclohexyl and the like.
  • aryl denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 6-14 carbon atoms in which at least one ring is aromatic in nature, for example phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or indanyl. Preferred is the phenyl group.
  • heteroaryl denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 5-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, for example quinoxalinyl, dihydroisoquinolinyl, pyrazin-2-yl, pyrazolyl, 2,4-dihydro-pyrazol-3-one, pyridinyl, isoxazolyl, pyridyl, pyrimidin-4-yl, pyrimidin-5-yl, [1,2.4]triazol-1-yl, [1,6]naphthyridin-2-yl, tetrazolyl, thiazolyl, imidazol-1-yl, Preferred heteroaryl group is pyridine-2, 3 or 4-yl or pyrimidinyl.
  • five or six membered heterocyclyl denotes a five or six membered alkyl ring, wherein one or two carbon atoms are replaced by N, S or O, for example the following groups: morpholinyl, piperazinyl, pyrrolidinyl, piperidin-1-yl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidin-4-yl or 1,1-dioxo- ⁇ 6 -thiomorpholinyl.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • the compounds of formula I-A can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
  • the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • the present compounds of formula I-A and their pharmaceutically acceptable salts may be prepared by methods, known in the art, for example by the process variant described below, which process comprises
  • Nucleophilic aromatic substitution reaction Coupling a compound of formula XIII with heteroaromatic chlorides and/or methylsulfones
  • N-Benzyl pyrrolidine derivatives (2 mmol) were dissolved in toluene (10 mL) and treated with NEt(iProp) 2 (6 mmol) and 1-chloroethylchloroformat (6 mmol) at 100 °C for 1.5 h. The solvent was evaporated, the residue taken up in MeOH (15 mL) and heated to reflux for 3 h. After evaporation of the solvent the residue was subjected to column chromatography to yield the de-benzylated product.
  • (3SR,4RS) ⁇ 3-(3,4-Dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl ⁇ -(4-methanesulfonyl-piperazin-1-yl)-methanone and (3SR,4RS) ⁇ 3-(3,4-Dichloro-phenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl ⁇ -(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl ester (4.0 g, 0.009 mmol) were dissolved in a 2.0 M solution of MeNH 2 in THF (31 mL) in an autoclave and heated to 80° C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, heptane/ethyl acetate 1:1) to yield the title compound (2.25 g, 81%) as a colorless oil.
  • Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (5.0 g, 0.0102 mmol) were dissolved in 2.0 M solution of MeNH 2 in THF (35 mL) in an autoclave and heated to 80 °C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, dichloro methane/methanol 0-> 20%) to yield the title compound (3.25 g, 91%) as a light yellow oil.
  • Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (2.0 g, 0.004 mmol) were dissolved in 2.0 M solution of EtNH 2 in THF (14 mL) in an autoclave and heated to 80° C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, heptane/ethyl acetate 1:1) to yield the title compound (1.2 g, 81 %) as a yellow oil.
  • the compounds of formula I-A and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of neurokinin 3 (NK-3) receptors. The compounds were investigated in accordance with the tests given hereinafter.
  • hNK3 receptor binding experiment were performed using [ 3 H]SR142801 (Catalog No. TRK1035, specific activity: 74.0 Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane isolated from HEK293 cells transiently expressing recombinant human NK3 receptor. After thawing, the membrane homogenates were centrifuged at 48,000 X g for 10 min at 4 °C, the pellets were resuspended in the 50 mM Tris-HCl, 4 mM MnCl 2 , 1 ⁇ M phosphoramidon, 0.1 % BSA binding buffer at pH 7.4 to a final assay concentration of 5 ⁇ g protein/well.
  • membranes were incubated with [ 3 H]SR142801 at a concentration equal to K D value of radioligand and 10 concentrations of the inhibitory compound (0.0003-10 ⁇ M) (in a total reaction volume of 500 ⁇ l) for 75 min at room temperature (RT).
  • RT room temperature
  • membranes were filtered onto unitfilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.3% PEI + 0.3% BSA, Packard BioScience, Meriden, CT) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer.
  • Nonspecific binding was measured in the presence of 10 ⁇ M SB222200 for both radioligands.
  • the radioactivity on the filter was counted (5 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 ⁇ l of microscint 40 (Canberra Packard S.A., Zurich, Switzerland) and shaking for 1 h.
  • the compounds of formula I-A as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I-A and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semiliquid or liquid polyols etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
  • Tablets of the following composition are manufactured in the usual manner: mg / tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight 100
  • Capsules of the following composition are manufactured: mg / capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsule fill weight 200
  • the active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelantine capsules.
  • the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 °C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Description

  • The present invention relates to a compounds of formula I- A
    Figure imgb0001
     wherein
    • A is -NR'-;
      R' is hydrogen or C1-7-alkyl;
    • Ar is C6-14-aryl or is a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 5-14 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N;
      Figure imgb0002
       is a five or six membered heterocyclic group;
      X1
      is N or CH; and
      X2
      is -N(R1)-, -CH2-, -O-, -S-, or -S(O)2-, R1 is hydrogen, C1-7-alkyl, S(O)2- C1-7-alkyl, C(O)- C1-7-alkyl, C(O)-C3-6-cycloalkyl optionally substituted by C1-7-alkyl; with the proviso that at least one of X1 or X2 contains a heteroatom,
      R2
      is C1-7-alkyl substituted by halogen, cyano or nitro;
      R3
      is halogen;
      R4
      is hydrogen or C1-7-alkyl;
      o
      is 1 or 2; in case o is 2, R2 may be the same or different;
      p
      is 1 or 2; in case p is 2, R3 may be the same or different;
    or a pharmaceutically active salt, a racemic mixture, an enantiomer, an optical isomer or a tautomeric form thereof.
  • The invention includes all stereoisomeric forms, including individual diastereoisomers and enantiomers of the compound of formula (I) as well as racemic and non-racemic mixtures
  • It has been found that the present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, bipolar disorders, anxiety and attention deficit hyperactivity disorder (ADHD).
  • The three main mammalian tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH2. As neurotransmitters, these peptides exert their biological activity via three distinct neurokinin (NK) receptors termed as NK-1, NK-2 and NK-3. SP binds preferentially to the NK-1 receptor, NKA to the NK-2 and NKB to the NK-3 receptor.
  • The NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain (Neurosci. Letters, 2000, 283, 185 -188 ; Exp. Opin. Ther. Patents 2000, 10, 939-960 ; Neuroscience, 1996, 74, 403-414 ; Neuropeptides, 1998, 32, 481-488).
  • Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1 % of the world's population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms).
  • For decades scientists and clinicians have made efforts with the aim of discovering an ideal agent for the pharmacological treatment of schizophrenia. However, the complexity of the disorders, due to a wide array of symptoms, has hampered those efforts. There are no specific focal characteristics for the diagnosis of schizophrenia and no single symptom is consistently present in all patients. Consequently, the diagnosis of schizophrenia as a single disorder or as a variety of different disorders has been discussed but not yet resolved. The major difficulty in the development of a new drug for schizophrenia is the lack of knowledge about the cause and nature of this disease. Some neurochemical hypotheses have been proposed on the basis of pharmacological studies to rationalize the development of a corresponding therapy: the dopamine, the serotonin and the glutamate hypotheses. But taking into account the complexity of schizophrenia, an appropriate multireceptor affinity profile might be required for efficacy against positive and negative signs and symptoms. Furthermore, an ideal drug against schizophrenia would preferably have a low dosage allowing once-per-day dosage, due to the low adherence of schizophrenic patients.
  • In recent years clinical studies with selective NK1 and NK2 receptor antagonists appeared in the literature showing results for the treatment of emesis, depression, anxiety, pain and migraine (NK1) and asthma (NK2 and NK1). The most exciting data were produced in the treatment of chemotherapy-induced emesis, nausea and depression with NK1 and in asthma with NK2- receptor antagonists. In contrast, no clinical data on NK3 receptor antagonists have appeared in the literature until 2000. Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identified potent and selective non-peptide antagonist described for the NK3 tachykinin receptor for the potential treatment of schizophrenia, which was reported in the literature (Current Opinion in Investigational Drugs, 2001,2(7), 950-956 and Psychiatric Disorders Study 4, Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Massachusetts ). The proposed drug SR 142,801 has been shown in a phase II trial as active on positive symptoms of schizophrenia, such as altered behaviour, delusion, hallucinations, extreme emotions, excited motor activity and incoherent speech, but inactive in the treatment of negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits.
  • The neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, as well as in schizophrenia, Exp. Opinion.Ther. Patents (2000), 10(6), 939-960 and Current Opinion in Investigational Drugs, 2001, 2(7), 950-956 956 and Psychiatric Disorders Study 4, Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Massachusetts).
  • Objects of the present invention are novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as depression, pain, bipolar disorders, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).
  • The preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, schizophrenia, bipolar disorders, anxiety and attention deficit hyperactivity disorder (ADHD).
  • The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
  • As used herein, the term "lower alkyl" denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
  • The term "lower alkyl substituted by halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2CF3, -CH2CF2CF3 and the like. Preferred lower alkyl substituted by halogen groups are groups having 1-4 carbon atoms.
  • The term "halogen" denotes chlorine, iodine, fluorine and bromine.
  • The term "cycloalkyl" denotes a saturated carbon ring containing from 3-6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclpentyl or cyclohexyl and the like.
  • The term "aryl" denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 6-14 carbon atoms in which at least one ring is aromatic in nature, for example phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or indanyl. Preferred is the phenyl group.
  • The term "five or six membered heteroaryl" denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 5-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, for example quinoxalinyl, dihydroisoquinolinyl, pyrazin-2-yl, pyrazolyl, 2,4-dihydro-pyrazol-3-one, pyridinyl, isoxazolyl, pyridyl, pyrimidin-4-yl, pyrimidin-5-yl, [1,2.4]triazol-1-yl, [1,6]naphthyridin-2-yl, tetrazolyl, thiazolyl, imidazol-1-yl, Preferred heteroaryl group is pyridine-2, 3 or 4-yl or pyrimidinyl.
  • The term "five or six membered heterocyclyl" ring denotes a five or six membered alkyl ring, wherein one or two carbon atoms are replaced by N, S or O, for example the following groups: morpholinyl, piperazinyl, pyrrolidinyl, piperidin-1-yl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidin-4-yl or 1,1-dioxo-λ6-thiomorpholinyl.
  • The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
    In detail, preferred are compounds of formula I-A, wherein
    Figure imgb0003
     for example
    • (3SR,4RS)-[3-(3,4-dichloro-phenyl)-4-(4-trifluoromethyl-phenylsulfanylmethyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-[3-(4-chloro-phenylsulfanylmethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-4-[4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethylsulfanyl]-benzonitrile
    • (3SR,4RS)-[3-(3,4-dichloro-phenyl)-4-(5-trifluoromethyl-pyridin-2-ylsulfanylmethyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-[3-(5-chloro-pyridin-2-ylsulfanylmethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-[3-(3,4-dichloro-phenyl)-4-[(5-nitro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3S,4S)-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfo nyl-p iperazin-1-yl)-methanone
    • (3R,4R)-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-{3-(3,4-dichloro-phenyl)-4-[(4-trifluoromethyl-phenylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-[3-[(5-chloro-pyridin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • (3SR,4RS)-2-{[4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
    • (3SR,4RS) 6-{1-(RS)-[4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethylamino}-nicotinonitrile and (3SR,4RS) 6-{1-(SR)-[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethylamino}-nicotinonitrile
    • (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone and (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone or
    • (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone.
    Further preferred are compounds of formula I-A, wherein
    Figure imgb0004
     for example
    • (3SR,4RS)-1-(4-{-3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
    • (3SR,4RS)-{1-{4-[3-[(5-chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-ethanone or
    • (3SR,4RS) 1-(4-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone.
    Further preferred are compounds of formula I-A, wherein
    Figure imgb0005
     for example
    • (3SR,4RS)-(3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-(1-methyl-cyclopropyl)-methanone
    • (3SR,4RS)-{3-[(5-chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • (3SR,4RS) {3-(4-chloro-phenyl)-4-[(5-chloro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • (3SR,4RS) {3-(4-fluoro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • (3SR,4RS) [4-(3-(4-fluoro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
    • 6-({(3S,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile
    • [4-((3S,4S)-3-(4-chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
    • ((3S,4S)-3-(4-chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • {(3S,4S)-3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • ((3S,4S)-3-(3,4-dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    • [4-((3S,4S)-3-(3,4-dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
    • 6-({(3S,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile or
    • {4-[(3S,4S)-3-{[(5-chloro-pyridin-2-yl)-methyl-amino]-methyl}-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone.
  • The preparation of compounds of formula I-A of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.
  • The compounds of formula I-A can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
  • The present compounds of formula I-A and their pharmaceutically acceptable salts may be prepared by methods, known in the art, for example by the process variant described below, which process comprises
    1. a) coupling a compound of formula
      Figure imgb0006
       with hal-(R2)o
      to a compound of formula
      Figure imgb0007
       wherein the definitions are described above, or
    2. b) coupling a compound of formula
      Figure imgb0008
       with a compound of formula
      Figure imgb0009
       to a compound of formula
      Figure imgb0010
       wherein the definitions are described above, and
      if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
  • The preparation of compounds of formula I is further described in more detail in the following schemes and examples.
    • General procedure I Amid coupling (pyrrolidine XI, XVI, XXII, XXX, XXXVI, XXXVIII, XLVII or LVI and carboxylic acid)
  • To a stirred solution of a carboxylic acid derivative (commercially available or known in the literature) (1 mmol) in 10 mL ofCH2Cl2 was added (1.3 mmol) ofEDC, (1.3 mmol) ofHOBt and Et3N (1.3 mmol). After one hour at RT, was added a corresponding pyrrolidine intermediate. The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 a concentrated under vacuo. Flash chromatography or preparative HPLC afforded the title compound.
    • General procedure II Coupling between a compound of formula XI, XVI, XXII, XXX, XXXVI, XXXVIII, XLVII or LVI and an acid chloride or carbamoyl chloride
  • A solution of the pyrrolidine (1 mmol) of formula (v.s.) in CH2Cl2 (10 mL) was treated with Et3N (1.2 mmol) and an acid chloride or carbamoyl chloride (1.2 mmol) and stirred at RT overnight. The reaction mixture was then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Purification by preparative HPLC yielded the title compound.
    • General procedure IV Nucleophilic aromatic substitution reaction: Coupling a compound of formula XIII with heteroaromatic chlorides and/or methylsulfones
  • A solution of amine XIII or XIV (1 mmol), triethylamine (0.4 mL, 2 mmol) and a heteroaromatic chloride (1 mmol) in DMSO (0.5 mL) in a high pressure glass vial is heated at 150-160 °C for several hours, depending on the nature of the compound. After the reaction ran to completion it was diluted with water, extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. Column chromatography yielded the title compound.
    • General procedure V Cleavage of the n-benzyl group with 1-chloroethylchloroformat and Methanol
  • N-Benzyl pyrrolidine derivatives (2 mmol) were dissolved in toluene (10 mL) and treated with NEt(iProp)2 (6 mmol) and 1-chloroethylchloroformat (6 mmol) at 100 °C for 1.5 h. The solvent was evaporated, the residue taken up in MeOH (15 mL) and heated to reflux for 3 h. After evaporation of the solvent the residue was subjected to column chromatography to yield the de-benzylated product.
    • General procedure VI Nucleophilic substitution reaction: Coupling a compound of formula XIX with anilines and heteroaromatic amines
  • To a stirred solution of tosylate XIX (1 mmol) and potassium carbonate (3 mmmol) in DMF (5 mL) at RT were added an anilin derivative of formula (3 mmol). Stirring was continued for several hours, depending on the nature of the aniline derivative, at 120 °C. The solvent was evaporated and the residue taken up in ethyl acetate. After washing with H2O the organic phase was dried over Na2SO4, filtered and concentrated. Column chromatography of the residue yielded the title compound.
    Figure imgb0011
     wherein (R3)p is 3,4-di-Cl and the other substituents are as described above.
    • Pyrrolidine intermediates of formula XIII
  • Figure imgb0012
    • a) (3SR,4RS)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile
  • A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (10.25 g, 43 mmol) in CH2Cl2 (55 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(3,4-dichloro-phenyl)-acrylnitrile (5.70 g, 29 mmol) and trifluoroacetic acid (0.22 mL, 3 mmol) in CH2Cl2 (10 mL) at 0 °C. The ice bath was removed, and the solution was stirred at 25 °C for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2) afforded the title compound (7.0 g, 73 %) as a colorless oil. ES-MS m/e: 332.3 (M+H+).
    • b) (3SR,4RS)-4-(3,4-Dichloro-phenyl)-pyrrolidine-3-carbonitrile
  • To a solution of (3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile (2.0 g, 6.6 mmol) dissolved in CH3CN (30 mL) was added 2,2,2-trichloroethyl chloroformate (1.22 mL, 9.91 mmol) and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the residue was dissolved in AcOH (25 mL) before a total of 1.20 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and the crude reaction product obtained used in the next reaction step, yielding 0.6 g (55 %) of the title compound as a light yellow oil. ES-MS m/e: 242.1 (M+H+).
    • c) (3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidine-3-carbonitrile
  • Using the general procedure II, the coupling between (3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile (0.60 g, 2.0 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (0.63 g, 2.7 mmol) (CAS-RN 65463-96-9) yielded the title product (0.68 g, 63 %) as a light yellow foam after purification by flash chromatography (SiO2, EtOAc/heptane 1:1). ES-MS m/e: 432.1 (M+H+).
    • d) [(3RS,4SR)-[3-Aminomethyl-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • To a stirred solution of (3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidine-3-carbonitrile (0.1 g, 0.23 mmol) in tetrahydrofuran (1.0 mL) at 0 °C was added BH3 in tetrahydrofuran (0.55 mL, 0.55 mmol). After 2 hours of stirring at ambient temperature the reaction mixture was quenched with MeOH and the volatiles were removed under vacuo. The residue was taken up in H2O, extracted with EtOAc and the combined organic phases were dried over Na2SO4. Flash chromatography (SiO2, EtOAc, then CH2Cl2/MeOH 19:1) yielded the title product (0.57 g, 56 %) as a colorless oil. ES-MS m/e: 436.1 (M+H+).
    • Example 7 (3SR,4RS)-[3-(3,4-Dichloro-phenyl)-4-[(5-nitro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0013
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3RS,4SR)- [3-Aminomethyl-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • Heteroaromatic chloride: 2-Chloro-4-nitropyridine
    • ES-MS m/e: 557.2 (M+H+).
    Example 8 (3SR,4RS)-[3-(3,4-Dichloro-phenyl)-4-[(5-nitro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0014
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3RS,4SR)- [3-Aminomethyl-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • Heteroaromatic chloride: 2-Chloro-4-cyanopyridine
    • ES-MS m/e: 536.9 (M+H+).
    Figure imgb0015
     wherein (R3)p is 3,4-di-Cl and the other substituents are as described above. Pyrrolidine intermediates of formula XIV
  • Figure imgb0016
    • [(3RS,4SR)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methylamine
  • To a stirred solution of (3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile (13 g, 0.39 mol) in tetrahydrofuran (250 mL) at 0 °C was added portion-wise LiAlH4 (1.56 g, 0.41 mol). After 2 hours of stirring at 0 °C the reaction mixture was quenched with water (50 mL) and 5N aqueous NaOH (12 mL) and stirred 30 min. The residue was extracted with EtOAc and the combined organic phases were dried over Na2SO4, filtered and the volatiles removed under vacuo to yield the crude title product (12.5 g, 95 %) as a yellow oil which was used directly in the next reaction steps. ES-MS m/e: 336.4 (M+H+).
    • Example 9 (3SR,4RS)-[1-(4-{3-(3,4-Dichloro-phenyl)-4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Figure imgb0017
    • a) (3SR,4RS)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-fluoro-pyrimidin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3RS,4SR)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methylamine
    • Heteroaromatic chloride: 2-Chloro-4-fluoropyrimidine
    • ES-MS m/e: 432.5 (M+H+).
    b) (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-fluoro-pyrimidin-2-yl)-amine
  • N-Benzyl cleavage according to General Procedure V:
    • N-Benzyl derivative: (3SR,4RS)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-fluoro-pyrimidin-2-yl)-amine
    • ES-MS m/e: 342.4 (M+H+).
    c) (3SR,4RS)-[1-(4-{3-(3,4-Dichloro-phenyl)-4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-fluoro-pyrimidin-2-yl)-amine
    • Acid chloride: 1-Acetylisonicopecotoylchloride
    • ES-MS m/e: 494.2 (M+H+).
    Example 11 (3SR,4RS)-1-(4-{3-(3,4-Dichloro-phenyl)-4-[(6-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Figure imgb0018
    • a) (3SR,4RS)-[1-Benzyl-4-(3,4-dichloro-phenyl-pyrrolidin-3-ylmethyl]-(6-trifluoromethyl-pyrimidin-4-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3RS,4SR)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methylamine
    • Heteroaromatic chloride: 4-Chloro-6-trifluoromethylpyrimidine (CAS RN: 37552-81-1)
    • ES-MS m/e: 482.5 (M+H+).
    b) (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(6-trifluoromethyl-pyrimidin-4-yl-amine
  • N-Benzyl cleavage according to General Procedure V:
    • N-Benzyl derivative: (3SR,4RS)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(6-trifluoromethyl-pyrimidin-4-yl)-amine
    • ES-MS m/e: 392.4 (M+H+).
    c) (3SR,4RS)-[1-(4-{3-(3,4-Dichloro-phenyl)-4-[(6-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(6-trifluoromethyl-pyrimidin-4-yl)-amine
    • Acid chloride: 1-Acetylisonicopecotoylchloride
    • ES-MS m/e: 544.1 (M+H+).
    Example 12 (3SR,4RS)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0019
    • a) (3SR,4RS)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3RS,4SR)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methylamine
    • Heteroaromatic chloride: 2-Chloro-5-trifluoromethylpyridine (CAS RN: 52334-81-3)
    • ES-MS m/e: 481.5 (M+H+).
    b) (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
  • N-Benzyl cleavage according to General Procedure V:
    • N-Benzyl derivative: (3SR,4RS)-[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
    • ES-MS m/e: 391.4 (M+H+).
    c) (3SR,4RS)-(3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carbamoyl chloride: 4-Methanesulfonyl-piperazine-1-carbonyl chloride (CAS-RN 65463-96-9)
    • ES-MS m/e: 579.6 (M+H+).
    Example 13 (3S,4S)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • (3SR,4RS)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone (150 mg) were separated (HPLC, Chiralpak AD column, 30 % iPrOH in heptane) to yield the title compound as a colorless foam (1.fraction eluted).
    ES-MS m/e: 580.2 (M+H+)
    • Example 14 (3R,4R)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • (3SR,4RS)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone (150 mg) were separated (HPLC, Chiralpak AD column, 30 % iPrOH in heptane) to yield the title compound as a colorless foam (2.fraction eluted).
    ES-MS m/e: 580.2 (M+H+)
    • Example 15 (3SR,4RS)-3-(3,4-Dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0020
  • (3SR,4RS)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone (75 mg, 0.13 mmol) were dissolved in DMF (2 mL) and treated with NaH (55 % dispersion in oil) (6.0 mg, 0.14 mmol) at ambient temperature. After 5min methyl iodide (0.01 mL, 0.14 mmol) was added and the reaction mixture was stirred over night. After quenching with water and extraction with ethyl acetate (3x 10 mL) the combined organic phases were dried on sodium sulfate and filtered. After evaporation of the solvent the crude product was subjected to column chromatography (silica gel, ethyl acetate) to yield the title product (66 %) as a light yellow oil. ES-MS m/e: 594.2 (M+H+).
    • Example 19 (3SR,4RS)-1-(4-{-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Figure imgb0021
  • Coupling between a compound of formula XVI and an acid chloride according to General procedure II
    • Amine: (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Acid chloride: 1-Acetylisonicopecotoylchloride
    • ES-MS m/e: 543.2 (M+H+).
    Example 21 (3SR,4RS)-(3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-(1-methyl-cyclopropyl)-methanone
  • Figure imgb0022
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (described herein below)
    • ES-MS m/e: 583.1 (M+H+).
    a)1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester
  • Amid coupling according to General procedure I
    • Amine: Ethyl isonipecotate (CAS RN: 1126-09-6)
    • Carboxylic acid: 1-Methylcyclopropane-carboxylic acid (CAS RN: 6914-76-7)
    • ES-MS m/e: 240.4 (M+H+).
    b)1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid:
  • 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (6.34 g, 26.5 mmol) and LiOH (1.67 g, 39.7 mmol) were stirred in a mixture of ethanol (30 mL), THF (30 mL) and water (15 mL) for 90 min at ambient temperature. After evaporation of the volatiles the residue was taken up in dichloro methane and extracted with 1N HCl. The organic phase was dried over sodium sulfate, filtered and evaporated to yield the title product (4.8 g, 86 %) as colorless solid.
    ES-MS m/e: 210.2 (M-H)-.
    Figure imgb0023
     wherein (R3)p is 3,4-di-Cl and the other substituents are as described above.
    • Preparation of (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester:
  • Figure imgb0024
    • a) (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methanol
  • (3SR,4RS) 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (3.6 g, 0.01 mol) were dissolved in THF (70 mL). At 0° C LiAlH4 (0.38 g, 0.01 mol) was added portion wise. After stirring at 0° C for 4 h water (3 mL), then 5N NaOH (3 mL) and additional water (9 mL) was added. After stirring at ambient temperature for 30 min the mixture was extracted with ethyl acetate (3x 10 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a light yellow oil (3.0 g, 94 %) and directly used in the next step.
    ES-MS m/e: 337.5 (M+H+).
    • b) (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
  • (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methanol (2.9 g, 9 mmol) were dissolved in dichloro methane (60 mL) and cooled to 0 °C. Then triethyl amine (1.6 mL, 11 mmol) and p-TosCl (1.81 g, 9.9 mmol) were added. The reaction mixture was allowed to slowly warm up to ambient temperature and stirred over night. Then the volatiles were removed and the residue directly subjected to column chromatography (silica gel, heptane, heptane/ethyl acetate 9:1/4:1/1:1) to yield the title product (2.5 g, 59 %) as a colorless oil.
    ES-MS m/e: 491.5 (M+H+).
    • Example 24 (3SR,4RS)-{3-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0025
    • a) (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyrimidin-2-yl-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-chlorpyrimidine
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 448.9 (M+H+).
    b) (3SR,4RS) (5-Chloro-pyrimidin-2-yl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyrimidin-2-yl)-amine
    • ES-MS m/e: 358.9 (M+H+).
    c) (3SR,4RS)-{3-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS) (5-Chloro-pyrimidin-2-yl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 550.3 (M+H+).
    Example 25 (3SR,4RS)-{1-{4-[3-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-ethanone
  • Figure imgb0026
  • Coupling between a compound of formula XVI and an acid chloride according to General procedure II
    • Amine: (3SR,4RS) (5-Chloro-pyrimidin-2-yl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
    • Acid chloride: 1-Acetylisonicopecotoylchloride
    • ES-MS m/e: 510.2 (M+H+).
    Example 28 (3SR,4RS)-{3-(3,4-Dichloro-phenyl)-4-[(4-trifluoromethyl-phenylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0027
    • a) (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(4-trifluoromethylphenyl)-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 4-Aminobenzotrifluorid
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 480.5 (M+H+).
    b) (3SR,4RS) [4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(4-trifluoromethyl-phenyl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(4-trifluoromethyl-phenyl)-amine
    • ES-MS m/e: 390.4 (M+H+).
    c) (3SR,4RS)-{3-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS) [4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(4-trifluoromethyl-phenyl)-amine
    • Carbamoyl chloride: 4-Methanesulfonyl-piperazine-1-carbonyl chloride (CAS-RN 65463-96-9)
    • ES-MS m/e: 579.2 (M+H+).
    Example 29 (3SR,4RS)-[3-[(4-Chloro-phenylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0028
    • a) (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(4-chloro-phenyl)-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 4-Chloroaniline
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 446.9 (M+H+).
    b) (3SR,4RS) (4-Chloro-phenyl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(4-chloro-phenyl)-amine
    • ES-MS m/e: 356.8 (M+H+).
    c) (3SR,4RS)-[3-[(4-Chloro-phenylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS) 4-Chloro-phenyl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
    • Carbamoyl chloride: 4-Methanesulfonyl-piperazine-1-carbonyl chloride (CAS-RN 65463-96-9)
    • ES-MS m/e: 547.1 (M+H+).
    Example 30 (3SR,4RS)-[3-[(5-Chloro-pyridin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0029
    • a) (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-chloropyridine
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 447.9 (M+H+).
    b) (3SR,4RS) (5-Chloro-pyridin-2-yl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-amine
    • ES-MS m/e: 357.8 (M+H+).
    c) (3SR,4RS)-[3-[(5-Chloro-pyridin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS)(5-Chloro-pyridin-2-yl)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amine
    • Carbamoyl chloride: 4-Methanesulfonyl-piperazine-1-carbonyl chloride (CAS-RN 65463-96-9)
    • ES-MS m/e: 546.1 (M+H+).
    Example 31 (3SR,4RS)-2-{[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
  • Figure imgb0030
    • a) (3SR,4RS) 2-{[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-cyanopyrimidine
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 439.5 (M+H+).
    b) (3SR,4RS) 2-{[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) 2-{[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
    • ES-MS m/e: 349.4 (M+H+).
    c) (3SR,4RS)-2-{[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS) 2-{[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
    • Carbamoyl chloride: 4-Methanesulfonyl-piperazine-1-carbonyl chloride (CAS-RN 65463-96-9)
    • ES-MS m/e: 538.2 (M+H+).
    Example 32 (3SR,4RS) 5-{[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-amino}-pyrazine-2-carbonitrile
  • Figure imgb0031
    • a) (3SR,4RS) 5-{[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrazine-2-carbonitrile
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-cyanopyrazine
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 439.5 (M+H+).
    b) (3SR,4RS) 5-{[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrazine-2-carbonitrile
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) 5-{[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrazine-2-carbonitrile
    • ES-MS m/e: 349.4 (M+H+).
    c) (3SR,4RS) 5-([4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-amino}-pyrazine-2-carbonitrile
  • Coupling between a compound of formula XVI and an acid chloride or carbamoyl chloride according to General procedure II
    • Amine: (3SR,4RS) 5-{[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-pyrazine-2-carbonitrile
    • Carbamoyl chloride: 4-Methanesulfonyl-piperazine-1-carbonyl chloride (CAS-RN 65463-96-9)
    • ES-MS m/e: 538.2 (M+H+).
    Example 33 (3SR,4RS) 1-(4-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Figure imgb0032
    • a) (3SR,4RS) [1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-trifluoromethylpyrimidine (CAS RN:69034-08-8)
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 482.5 (M+H+).
    b) (3SR,4RS) [4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) 5-{[1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • ES-MS m/e: 392.4 (M+H+).
    c) (3SR,4RS) 1-(4-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
  • Coupling between a compound of formula XVI and an acid chloride according to General procedure II
    • Amine: (3SR,4RS) [4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Acid chloride: 1-Acetylisonicopecotoylchloride
    • ES-MS m/e: 544.1 (M+H+).
    Example 34 (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0033
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS) [4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 584.0 (M+H+).
    Figure imgb0034
     wherein (R3)p is 3,4-di-Cl and the other substituents are as described above.
    Figure imgb0035
     a) 1-[(3SR,4RS)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone
  • A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.78 g, 0.138 mol) in CH2Cl2 (50 mL) was added drop wise, over a 30 minutes period, to a stirred solution of (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (CAS RN: 55420-70-7) (19.80 g, 0.092 mol) and trifluoroacetic acid (1.05 mL, 0.009 mol) in CH2Cl2 (100 mL) at 0 °C. The ice bath was removed, and the solution was stirred at 25 °C for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:2) afforded the title compound (28.3 g, 88 %) as a yellow oil. ES-MS m/e: 348.2 (M+H+).
    • b) 1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethanone
  • To a solution of 1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone 4.00 g (9.20 mmol) dissolved in CH3CN (50 mL) was added 2.48 mL (18.40 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 3 hours at RT. Volatiles were removed under vacuo, and the residue was dissolved in AcOH (30 mL) before a total of 1.5 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1 to 8:2) yielded the title compound (1.50 g, 63 %) as a colorless oil. ES-MS m/e: 258.0 (M+H+).
    • c) 1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl-ethanone
  • Using the general procedure II, the coupling between 1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone (1.88 g, 7.28 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (1.98 g, 8.74 mmol) yielded the title product (2.40 g, 74 %) as a colorless oil after purification by flash chromatography (SiO2, EtOAc). ES-MS m/e: 449.5 (M+H+).
    • d)1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone oxime
  • 1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone (0.87 g, 2 mmol), hydroxylamine hydrochloride (0.28 g, 2.05 mmol) and sodium acetate (0.33 g, 2.06 mmol) were dissolved in ethanol (9.0 mL) and heated to reflux for 2h. After cooling to ambient temperature water (20 mL) was added. The mixture was extracted with ethyl acetate (3x10 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (silica gel, ethyl acetate) to yield the title compound as a colorless foam (0.74 g, 82 %). ES-MS m/e: 437.5 (M+H+).
    • e)[(3SR,4RS)-3-(1-(RS)-Amino-ethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone and [(3SR,4RS)-3-(1-(SR)-Amino-ethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • 1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethanone oxime (0.14 g, 0.3 mmol) were dissolved in methanol (10 mL) and treated under an atmosphere of H2 (5 bar) at ambient temperature for several hours. The crude product was, after filtration and evaporation of the solvent, subjected to column chromatography (silica gel, dichloro methane, dichloro methane/methanol 2 %, 5 %) to yield the title product as a mixture of diastereomers as a colorless foam (0.082 g, 60%). ES-MS m/e: 450.5 (M+H+).
    • Example 36 (3SR,4RS) 6-{1-(RS)-[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethylamino}-nicotinonitrile and (3SR,4RS) 6-{1-(SR)-[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethylamino}-nicotinonitrile
  • Figure imgb0036
  • Nucleophilic aromatic substitution reaction: Coupling of XXV with heteroaromatic chlorides and/or methylsulfones according to General procedure IV
    • Amine: [(3SR,4RS)-3-(1-(RS)-Amino-ethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone and [(3SR,4RS)-3-(1-(SR)-Amino-ethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • Heteroaryl chloride: 6-Chloro-3-pyridincarbonitrile
    • ES-MS m/e: 551.2 (M+H+).
    Example 37 (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone and (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0037
  • Nucleophilic aromatic substitution reaction: Coupling of XXV with heteroaromatic chlorides and/or methylsulfones according to General procedure IV
    • Amine: [(3SR,4RS)-3-(1-(RS)-Amino-ethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone and [(3SR,4RS)-3-(1-(SR)-Amino-ethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    • Heteroaryl chloride: 2-Chloro-5-(trifluoromethyl)-pyridine
    • ES-MS m/e: 594.2 (M+H+).
    Example 38 (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0038
  • (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone and (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone (150 mg) were separated (HPLC, YMC Pack SIL column) to yield the title compound as a colorless foam (1.fraction eluted). ES-MS m/e: 594.2 (M+H+).
    • Example 39 (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
  • Figure imgb0039
  • (3SR,4RS) {3-(3,4-Dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone and (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone (150 mg) were separated (HPLC, YMC Pack SIL column) to yield the title compound as a colorless foam (2.fraction eluted). ES-MS m/e: 594.2 (M+H+).
    Figure imgb0040
     wherein (R3)p is 4-Cl and the other substituents are as described above.
    • Preparation of (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl ester:
  • Figure imgb0041
    • a) (3SR,4RS) [1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methanol
  • (3SR,4RS) 1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (CAS RN: 80896-63-5) (30 g, 0.087 mol) were dissolved in THF (400 mL). At 0° C LiAlH4 (3.5 g, 0.092 mol) was added portion wise. After stirring at 0 °C for 4 h water (18 mL), then 5N NaOH (18 mL) and additional water (54 mL) was added. After stirring at ambient temperature for 1h the mixture was extracted with ethyl acetate (3x 100 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a white solid (24.6 g, 93 %) and directly used in the next step.
    ES-MS m/e: 302.9 (M+H+).
    • b) (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl ester
  • (3SR,4RS) [1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methanol (24.5 g, 0.081 mmol) were dissolved in dichloro methane (550 mL) and cooled to 0 °C. Then triethyl amine (13.5 mL, 0.097 mol) and p-TosCl (16.25 g, 0.085 mol) were added. The reaction mixture was allowed to slowly warm up to ambient temperature and stirred over night. Then the volatiles were removed and the residue directly subjected to column chromatography (silica gel, heptane, heptane/ethyl acetate 9:1/4:1/1:1) to yield the title product (24.4 g, 66 %) as a white solid.
    ES-MS m/e: 457.1 (M+H+).
    • Example 41 (3SR,4RS) {3-(4-Chloro-phenyl)-4-[(5-chloro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0042
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS)[4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 515.3 (M+H+).
    Example 43 (3SR,4RS) {3-(4-Chloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0043
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS)[4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 549.3 (M+H+).
    Example 45 (3SR,4RS) 6-({4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-amino)-nicotinonitrile
  • Figure imgb0044
  • Amid coupling (pyrrolidine V, X or XV and carboxylic acid) according to General procedure I
    • Amine: (3SR,4RS) 6-{[[4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-amino}-nicotinonitrile
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 506.3 (M+H+).
    Figure imgb0045
     wherein (R3)p is 4-F and the other substituents are as described above. Preparation of (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl ester and (3SR,4RS)[1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine:
  • Figure imgb0046
    • a) (3SR,4RS) [1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methanol
  • (3SR,4RS) 1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (CAS RN: 874990-58-6) (20 g, 0.061 mol) were dissolved in THF (600 mL). At 0 °C LiAlH4 (2.8 g, 0.073 mol) was added portion wise. After stirring at 0 °C for 4 h water (15 mL), then 5N NaOH (15 mL) and additional water (25 mL) was added. After stirring at ambient temperature for 1h the mixture was extracted with ethyl acetate (3x 50 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a light yellow oil (14.95 g, 86 %) and directly used in the next step.
    ES-MS m/e: 286.2 (M+H+).
    • b) (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl ester
  • (3SR,4RS) [1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methanol (14.95 g, 0.052 mmol) were dissolved in dichloro methane (200 mL) and cooled to 0 °C. Then triethyl amine (10.15 mL, 0.073 mol) and p-TosCl (12.98 g, 0.068 mol) were added. The reaction mixture was allowed to slowly warm to ambient temperature and stirred over night. Then the volatiles were removed and the residue directly subjected to column chromatography (silica gel, heptane, heptane/ethyl acetate 9:1/4:1/1:1) to yield the title product (10.8 g, 47 %) as a light yellow oil.
    ES-MS m/e: 440.3 (M+H+).
    • c) (3SR,4RS)[1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
  • (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl ester (5.0 g, 0.011 mmol) were dissolved in 2.0 M solution of MeNH2 in THF (36 mL) in an autoclave and heated to 80 °C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, dichloro methane, dichloro methane/methanol -> 4:1) to yield the title compound (2.6 g, 76 %) as a light yellow oil.
    ES-MS m/e: 299.3 (M+H+).
    • Example 46 (3SR,4RS) {3-(4-Fluoro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0047
    • a) (3SR,4RS) [1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-trifluoromethylpyrimidine (CAS RN:69034-08-8)
    • Tosylate: (3SR,4RS) Toluene-4-sulfonic acid-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 431.5 (M+H+).
    b) (3SR,4RS) [4-(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • ES-MS m/e: 341.3 (M+H+).
    c) (3SR,4RS) {3-(4-Fluoro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS) [4-(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 534.2 (M+H+).
    Example 47 (3SR,4RS) [4-(3-(4-Fluoro-phenyl)-4-{[methyl-(4-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
  • Figure imgb0048
    • a) [(3SR,4RS)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: (3SR,4RS)[1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic methylsulfone: 2-Methanesulfonyl-5-trifluoromethyl-pyrimidine (CAS RN: 361389-88-0)
    • ES-MS m/e: 445.2 (M+H+).
    b) [(3SR,4RS)-4-(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • ES-MS m/e: 355.2 (M+H+).
    c) (3SR,4RS) [4-(3-(4-Fluoro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl-piperidin-1-yl]-(1-methyl-cyclopropyl-methanone
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS) [4-(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 548.3 (M+H+).
    Example 48 (3SR,4RS) (3-(4-Fluoro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0049
    • a) [(3SR,4RS)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: (3SR,4RS)[1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic methylsulfone: 2-Methanesulfonyl-5-trifluoromethyl-pyrimidine
    • ES-MS m/e: 444.5 (M+H+).
    b) [(3SR,4RS)-4-(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: (3SR,4RS) [1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • ES-MS m/e: 354.2 (M+H+).
    c) (3SR,4RS) (3-(4-Fluoro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: (3SR,4RS) [4-(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 547.3 (M+H+).
    Figure imgb0050
     wherein (R3)p is 4-Cl and the other substituents are as described above.
    Figure imgb0051
     a) 1-Benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid
  • A solution ofN-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (201.6 g, 849 mmol) in CH2Cl2 (600 mL) was added dropwise over a 30 minutes period to a stirred solution of 3-(4-chlorophenyl)-2-propionic acid ethyl ester (125.9 g, 566 mmol) and trifluoroacetic acid (4.3 mL, 114 mmol) in CH2Cl2 (400 mL) at 0 °C. The ice bath was removed, and the solution was stirred at 25 °C for an additional 4h. It was then concentrated and the reaction mixture was taken up in dioxane (1.2 L). Then 1N NaOH (146 mL) were added and the mixture was stirred at ambient temperature for 72h. The volatiles were removed and the residue was extracted with TBDME and water. The organic phases were extracted with water and the combined aqueous phases were acidified with aqueous HCl (10 %). Upon stirring at ambient temperature over night a precipitation formed which was isolated, washed with water and ethanol and dried under high vacuum to yield the title product (148 g, 76%) as a colorless solid.
    ES-MS m/e: 314.8 (M+H+).
    • b) (3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid
  • A 185-ml stainless steel autoclave was charged under argon in a glove box (O2 content ≤ 2 ppm) with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (5.00 g, 15.1 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP] (3.8 mg, 5.0 µmol) (S/C 5'000) and methanol (150 mL). The asymmetric hydrogenation was run under 40 bar of hydrogen for 20 h at 30°C and additional 2 h at 60 °C to complete the conversion (>99.6 % conversion and 99.9% ee). After the pressure was released, the white suspension was stirred at 0-5 °C for 2 h, filtered off and the filter cake was washed with cold (0-5 °C) methanol (20 mL) and dried under vacuum at room temperature to yield the title product (4.75 g, 99 %) with 99 % purity and 99.9% ee. ES-MS m/e: 316.1 (M+H+).
    • c) (3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester
  • (3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (7.0 g, 22.0 mmol) were dissolved in methanol (75 mL) and at ambient temperature treated with sulfuric acid 97 % (2.4 mL). The reaction mixture was stirred at 60 °C for 18h. At 0 °C dichloro methane (150 mL) was added followed by aqueous sodium carbonate 10 % (150 mL) (final pH 11) under vigorous stirring. The phases were separated. The aqueous phase was washed with dichloro methane, the combined organic phases with water and brine and then dried on sodium sulfate. After filtration and evaporation of the solvent the title product was obtained as a light brown oil (7.0 g, 96 %) which was directly used in the next step. ES-MS m/e: 330.8 (M+H+).
    • d) (3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester
  • (3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (7.0 g, 21.0 mmol) were dissolved in methanol (60 mL) and treated with NaOMe (30 % in methanol, 0.9 mL, 4.50 mmol) for 24h at ambient temperature. The volatiles were removed and the residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1) to yield the title compound (5.9 g, 84 %) as a colorless oil. ES-MS m/e: 330.8 (M+H+).
    • e) [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methanol
  • (3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (5.8 g, 0.018 mol) were dissolved in THF (180 mL). At 0 °C LiAlH4 (0.70 g, 0.0185 mol) was added portion wise. After stirring at 0 °C for 4 h water (5 mL), then 5N NaOH (5 mL) and additional water (15 mL) was added. After stirring at ambient temperature for 30 min the mixture was extracted with ethyl acetate (3x 10 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a light yellow oil (5.2 g, 98 %) and directly used in the next step. ES-MS m/e: 302.8 (M+H+).
    • f) Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl ester
  • [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methanol (5.2 g, 17.0 mmol) were dissolved in dichloro methane (80 mL) and cooled to 0° C. Then triethyl amine (3.34 mL, 24.0 mmol) and p-TosCl (4.27 g, 22.0 mmol) were added. The reaction mixture was allowed to slowly warm to ambient temperature and stirred over night. Then the volatiles were removed and the residue directly subjected to column chromatography (silica gel, heptane, heptane/ethyl acetate 9:1/4:1) to yield the title product (5.2 g, 66 %) as a colorless oil.
    ES-MS m/e: 457.1 (M+H+).
    • g) [(3SAS)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
  • Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl ester (4.0 g, 0.009 mmol) were dissolved in a 2.0 M solution of MeNH2 in THF (31 mL) in an autoclave and heated to 80° C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, heptane/ethyl acetate 1:1) to yield the title compound (2.25 g, 81%) as a colorless oil.
    ES-MS m/e: 315.9 (M+H+).
    • Example 49 ((3S,4S)-3-(4-Chloro-phenyl)-4-{[(5-chloro-pyridin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0052
    • a) [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-methyl-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic methylsulfone: 2,5-Dichloro-pyridine
    • ES-MS m/e: 427.5 (M+H+).
    b) [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-methyl-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-methyl-amine
    • ES-MS m/e: 355.2 (M+H+).
    c) ((3S,4S)-3-(4-Chloro-phenyl)-4-{[(5-chloro-pyridin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-methyl-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 529.2 (M+H+).
    Example 51 6-({(3S,4S)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile
  • Figure imgb0053
    • a) 6-{[(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic chloride: 6-Chloro-3-pyridine carbonitrile (CAS RN: 33252-28-7)
    • ES-MS m/e: 427.5 (M+H+).
    b) 6-{[(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: 6-{[(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
    • ES-MS m/e: 327.92 (M+H+).
    c) 6-({(3S,4S)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile
  • Amid coupling according to General procedure I
    • Amine: 6-{[(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 520.3 (M+H+).
    Example 53 [4-((3S,4S)-3-(4-Chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
  • Figure imgb0054
    • a) [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-5-trifluoromethyl-pyridin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic chloride: 2-Chloro-5-trifluoromethyl pyridine (CAS RN: 52334-81-3)
    • ES-MS m/e: 461.0 (M+H+).
    b) [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • ES-MS m/e: 370.9 (M+H+).
    c) [4-((3S,4S)-3-(4-Chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 563.3 (M+H+).
    Example 55 ((3S,4S)-3-(4-Chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0055
    • a) [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic methylsulfone: 2-Methanesulfonyl-5-trifluoromethyl-pyrimidine (CAS RN: 361389-88-0)
    • ES-MS m/e: 462.0 (M+H+).
    b) [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • ES-MS m/e: 371.9 (M+H+).
    c) ((3S,4S)-3-(4-Chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 564.3 (M+H+).
    Figure imgb0056
     wherein (R3)p is 3,4-di-Cl and the other substituents are as described above.
    Figure imgb0057
     a) (3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester
  • (3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (CAS RN: 907184-53-6) (35.7 g, 0.102 mol) were dissolved in methanol (350 mL) and at ambient temperature treated with sulfuric acid 97% (10. 9mL). The reaction mixture was stirred at 60° C for 18h. At 0 °C dichloro methane (500 mL) was added followed by aqueous sodium carbonate 10 % (500 mL) (final pH 11) under vigorous stirring. The phases were separated. The aqueous phase was washed with dichloro methane, the combined organic phases with water and brine and then dried on sodium sulfate. After filtration and evaporation of the solvent the title product was obtained as a yellow oil (36.3 g, 98 %) which was directly used in the next step. ES-MS m/e: 365.3 (M+H+).
    • b) (3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester
  • (3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (37.5 g, 0.107 mol) were dissolved in methanol (300 mL) and treated with NaOMe (30 % in methanol, 2.97 mL, 0.016 mol) for 24 h at ambient temperature. The volatiles were removed and the residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1) to yield the title compound (32.0 g, 82 %) as a colorless oil. ES-MS m/e: 365.3 (M+H+).
    • c) [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methanol
  • (3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (28.5 g, 0.078 mol) were dissolved in THF (800 mL). At 0 °C LiAlH4 (3.12 g, 0.082 mol) was added portion wise. After stirring at 0° C for 4 h water (20 mL), then 5N NaOH (20 mL) and additional water (30 mL) was added. After stirring at ambient temperature for 30 min the mixture was extracted with ethyl acetate (3x 10 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a white solid (25.0 g, 95 %) and directly used in the next step. ES-MS m/e: 337.8 (M+H+).
    • d) Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
  • [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methanol (55.0 g, 0.164 mmol) were dissolved in dichloro methane (800 mL) and cooled to 0 °C. Then triethyl amine (31.74 mL, 0.24 mol) and p-TosCl (40.54 g, 0.213 mol) were added. The reaction mixture was allowed to slowly warm to ambient temperature and stirred over night. Then the volatiles were removed and the residue directly subjected to column chromatography (silica gel, heptane, heptane/ethyl acetate 9:1/4:1) to yield the title product (62 g, 77 %) as a white solid.
    ES-MS m/e: 491.1 (M+H+).
    • e) [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
  • Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (5.0 g, 0.0102 mmol) were dissolved in 2.0 M solution of MeNH2 in THF (35 mL) in an autoclave and heated to 80 °C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, dichloro methane/methanol 0-> 20%) to yield the title compound (3.25 g, 91%) as a light yellow oil.
    ES-MS m/e: 349.2 (M+H+).
    • f) [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-amine
  • Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (2.0 g, 0.004 mmol) were dissolved in 2.0 M solution of EtNH2 in THF (14 mL) in an autoclave and heated to 80° C over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, heptane/ethyl acetate 1:1) to yield the title compound (1.2 g, 81 %) as a yellow oil.
    ES-MS m/e: 364.2 (M+H+).
    • Example 57 {(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0058
    • a) [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Nucleophilic substitution reaction according to General Procedure VI
    • Aniline derivative: 2-Amino-5-trifluoromethylpyrimidine (CAS RN:69034-08-8)
    • Tosylate: Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester
    • ES-MS m/e: 482.5 (M+H+).
    b) [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • ES-MS m/e: 392.3 (M+H+).
    c) {(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 584.2 (M+H+).
    Example 59 ((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0059
  • {(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (30.0 mg, 0.051 mmol) were dissolved in DMF (1 mL) and treated with NaH (55 % dispersion in oil) (2.5 mg, 0.056 mmol) at ambient temperature. After 5min methyl iodide (3.5 µL, 0.056 mmol) were added and the reaction mixture was stirred over night. After quenching with water and extraction with ethyl acetate (3x 10 mL) the combined organic phases were dried on sodium sulfate and filtered. After evaporation of the solvent the crude product was subjected to column chromatography (silica gel, ethyl acetate) to yield the title product (19 mg, 62 %) as a colorless foam. ES-MS m/e: 598.3 (M+H+).
    • Example 61 ((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[ethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0060
    • a) [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-amine
    • Heteroaromatic methylsulfone: 2-Methanesulfonyl-5-trifluoromethyl-pyrimidine
    • ES-MS m/e: 510.4 (M+H+).
    b) [(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • ES-MS m/e: 420.3 (M+H+).
    c) ((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[ethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyrimidin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 612.2 (M+H+).
    Example 62 [4-((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
  • Figure imgb0061
    • a) [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic chloride: 2-Chloro-5-trifluoromethyl-pyridine
    • ES-MS m/e: 494.2 (M+H+).
    b) [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • ES-MS m/e: 404.3 (M+H+).
    c) [4-((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 597.3 (M+H+).
    Example 63 ((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[ethyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Figure imgb0062
    • a) [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-amine
    • Heteroaromatic chloride: 2-Chloro-5-trifluoromethyl-pyridine
    • ES-MS m/e: 509.2 (M+H+).
    b) [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyridin-2-yl)-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • ES-MS m/e: 420.3 (M+H+).
    c) ((3S,4S)-3-(3,4-Dichloro-phenyl)-4-{[ethyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
  • Amid coupling according to General procedure I
    • Amine: [(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-ethyl-(5-trifluoromethyl-pyridin-2-yl)-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 611.2 (M+H+).
    Example 64 6-({(3S,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile
  • Figure imgb0063
    • a) 6-{[(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic chloride: 6-Chloro-3-pyridine-carbonitrile
    • ES-MS m/e: 451.2 (M+H+).
    b) 6-{[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: 6-{[(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
    • ES-MS m/e: 361.2 (M+H+).
    c) 6-({(3S,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile
  • Amid coupling according to General procedure I
    • Amine: 6-{[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-nicotinonitrile
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 554.3 (M+H+).
    Example 66 {4-[(3S,4S)-3-{[(5-Chloro-pyridin-2-yl)-methyl-amino]-methyl}-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone
  • Figure imgb0064
    • a) [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-methyl-amine
  • Nucleophilic aromatic substitution according to General Procedure IV:
    • Amine: [(3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Heteroaromatic chloride: 2,5-Dichloro-pyridine (CAS RN: 16110-09-1)
    • ES-MS m/e: 462.2 (M+H+).
    b) (5-Chloro-pyridin-2-yl)-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
  • Cleavage of the n-benzyl group according to General Procedure V
    • Amine: [(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-chloro-pyridin-2-yl)-methyl-amine
    • ES-MS m/e: 372.0 (M+H+).
    c) {4-[(3S,4S)-3-{[(5-Chloro-pyridin-2-yl)-methyl-amino]-methyl}-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone
  • Amid coupling according to General procedure I
    • Amine: (5-Chloro-pyridin-2-yl)-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl]-methyl-amine
    • Carboxylic acid: 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid
    • ES-MS m/e: 563.2 (M+H+).
  • As mentioned earlier, the compounds of formula I-A and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of neurokinin 3 (NK-3) receptors. The compounds were investigated in accordance with the tests given hereinafter.
    • Experimental procedure
  • The compounds were investigated in accordance with the tests given hereinafter
    • [ 3H]SR142801 competition binding assay
  • hNK3 receptor binding experiment were performed using [3H]SR142801 (Catalog No. TRK1035, specific activity: 74.0 Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane isolated from HEK293 cells transiently expressing recombinant human NK3 receptor. After thawing, the membrane homogenates were centrifuged at 48,000 X g for 10 min at 4 °C, the pellets were resuspended in the 50 mM Tris-HCl, 4 mM MnCl2, 1 µM phosphoramidon, 0.1 % BSA binding buffer at pH 7.4 to a final assay concentration of 5 µg protein/well. For inhibition experiments, membranes were incubated with [3H]SR142801 at a concentration equal to KD value of radioligand and 10 concentrations of the inhibitory compound (0.0003-10 µM) (in a total reaction volume of 500 µl) for 75 min at room temperature (RT). At the end of the incubation, membranes were filtered onto unitfilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.3% PEI + 0.3% BSA, Packard BioScience, Meriden, CT) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 µM SB222200 for both radioligands. The radioactivity on the filter was counted (5 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 µl of microscint 40 (Canberra Packard S.A., Zurich, Switzerland) and shaking for 1 h. Inhibition curves were fitted according to the Hill equation: y = 100/(1+(x/IC50)nH), where nH = slope factor using Excel-fit 4 software (Microsoft). IC50 values were derived from the inhibition curve and the affinity constant (Ki) values were calculated using the Cheng-Prussoff equation Ki = IC50/(1+[L]/KD) where [L] is the concentration of radioligand and KD is its dissociation constant at the receptor, derived from the saturation isotherm. All experiments were performed in duplicate and the mean ± standard error (SEM) of the individual Ki values was calculated.
  • Some results of preferred compounds with a hNK-3 receptor affinity <0.10 µM were shown in the following table 1. Table 1
    Example Data Ki [µM] Example Data Ki [µM]
    30 0.0361
    31 0.08
    33 0.0075
    34 0.0062
    8 0.0711 36 0.0682
    12 0.02 37 0.0549
    13 0.0066 38 0.0223
    14 0.0924 41 0.0863
    15 0.0788 46 0.0228
    47 0.0716
    19 0.0103 51 0.0699
    53 0.0856
    21 0.0089 55 0.0429
    57 0.0018
    24 0.0165 59 0.0023
    25 0.0195
    62 0.0084
    64 0.0318
    28 0.0585 66 0.047
  • The compounds of formula I-A as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • The compounds of formula I-A and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semiliquid or liquid polyols etc.
  • Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
    • Example A
  • Tablets of the following composition are manufactured in the usual manner:
    mg / tablet
    Active substance 5
    Lactose 45
    Corn starch 15
    Microcrystalline cellulose 34
    Magnesium stearate 1
    Tablet weight 100
    • Example B
  • Capsules of the following composition are manufactured:
    mg / capsule
    Active substance 10
    Lactose 155
    Corn starch 30
    Talc 5
    Capsule fill weight 200
    The active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelantine capsules.
    • Example C
  • Suppositories of the following composition are manufactured:
    mg / supp.
    Active substance 15
    Suppository mass 1285
    Total 1300
  • The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 °C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Claims (11)

  1. A compound of formula I-A
    Figure imgb0065
     wherein
    A is -NR'-;
    R' is hydrogen or C1-7-alkyl;
    Ar is C6-14-aryl or is a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 5-14 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N;
    Figure imgb0066
     is a five or six membered heterocyclic group;
    X1 is N or CH; and
    X2 is -N(R1)-, -CH2-, -O-, -S-, or -S(O)2-, R1 is hydrogen, C1-7-alkyl, S(O)2- C1-7-alkyl, C(O)- C1-7-alkyl, C(O)-C3-6-cycloalkyl optionally substituted by C1-7-alkyl; with the proviso that at least one of X1 or X2 contains a heteroatom,
    R2 is C1-7-alkyl substituted by halogen, cyano or nitro;
    R3 is halogen;
    R4 is hydrogen or C1-7-alkyl;
    o is 1 or 2; in case o is 2, R2 may be the same or different;
    p is 1 or 2; in case p is 2, R3 may be the same or different;
    or a pharmaceutically active salt, a racemic mixture, an enantiomer, an optical isomer or a tautomeric form thereof.
  2. A compound of formula I-A according to claim 1, wherein
    Figure imgb0067
     is
    Figure imgb0068
  3. A compound of formula I-A according to claim 2, wherein the compounds are
    (3SR,4RS)-[3-(3,4-dichloro-phenyl)-4-(4-trifluoromethyl-phenylsulfanylmethyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-[3-(4-chloro-phenylsulfanylmethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-4-[4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethylsulfanyl]-benzonitrile
    (3SR,4RS)-[3-(3,4-dichloro-phenyl)-4-(5-trifluoromethyl-pyridin-2-ylsulfanylmethyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-[3-(5-chloro-pyridin-2-ylsulfanylmethyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-[3-(3,4-dichloro-phenyl)-4-[(5-nitro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3S,4S)-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3R,4R)-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-{3-(3,4-dichloro-phenyl)-4-[(4-trifluoromethyl-phenylamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-[3-[(5-chloro-pyridin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone
    (3SR,4RS)-2-{[4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-ylmethyl]-amino}-pyrimidine-5-carbonitrile
    (3SR,4RS) 6-{1-(RS)-[4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethylamino}-nicotinonitrile and (3SR,4RS) 6-{1-(SR)-[4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethylamino}-nicotinonitrile
    (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone and (3SR,4RS) {3-(3,4-dichlorophenyl)-4-[1-(SR)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone or
    (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[1-(RS)-(5-trifluoromethyl-pyridin-2-ylamino)-ethyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methanone.
  4. A compound of formula I-A according to claim 1, wherein
    Figure imgb0069
     is
    Figure imgb0070
  5. A compound of formula I-A according to claim 4, wherein the compounds are
    (3SR,4RS)-1-(4-{-3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
    (3SR,4RS)-{1-{4-[3-[(5-chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-ethanone or
    (3SR,4RS) 1-(4-{3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone.
  6. A compound of formula I-A according to claim 1, wherein
    Figure imgb0071
     is
    Figure imgb0072
  7. A compound of formula I-A according to claim 6, wherein the compounds are
    (3SR,4RS)-(3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-(1-methyl-cyclopropyl)-methanone
    (3SR,4RS)-{3-[(5-chloro-pyrimidin-2-ylamino)-methyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    (3SR,4RS) {3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    (3SR,4RS) {3-(4-chloro-phenyl)-4-[(5-chloro-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    (3SR,4RS) {3-(4-fluoro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1 yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    (3SR,4RS) [4-(3-(4-fluoro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
    6-({(3S,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile
    [4-((3S,4S)-3-(4-chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
    ((3S,4S)-3-(4-chloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    {(3S,4S)-3-(3,4-dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    ((3S,4S)-3-(3,4-dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyrimidin-2-yl)-amino]-methyl}-pyrrolidin-1-yl)-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone
    [4-((3S,4S)-3-(3,4-dichloro-phenyl)-4-{[methyl-(5-trifluoromethyl-pyridin-2-yl)-amino]-methyl}-pyrrolidine-1-carbonyl)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone
    6-({(3S,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-ylmethyl}-methyl-amino)-nicotinonitrile or
    {4-[(3S,4S)-3-{[(5-chloro-pyridin-2-yl)-methyl-amino]-methyl}-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone.
  8. A process for preparing a compound of formula Ia as defined in claim 1, which process comprises
    a) coupling a compound of formula
    Figure imgb0073
     with hal-Ar-(R2)o
    to a compound of formula
    Figure imgb0074
     wherein the definitions are described in claim 1, or
    b) coupling a compound of formula
    Figure imgb0075
     with a compound of formula
    Figure imgb0076
     to a compound of formula
    Figure imgb0077
     wherein the definitions are described in claim 1, and
    if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
  9. A medicament containing one or more compounds as claimed in any one of claims 1 - 6 and pharmaceutically acceptable excipients.
  10. A medicament according to claim 9 for use in the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, bipolar disorder, anxiety and attention deficit hyperactivity disorder (ADHD).
  11. The use of a compound as claimed in any one of claims 1 -6 for the manufacture of medicaments for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, bipolar disorder, anxiety and attention deficit hyperactivity disorder (ADHD).
EP10704808.4A 2009-02-18 2010-02-16 Pyrrolidine derivatives as nk3 receptor antagonists Not-in-force EP2398768B1 (en)

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